1. Field of the Invention
This invention relates to a biocompatible, hydrophilic, segmented block copolymer that comprises hard and soft segments in a predefined proportion. The copolymers have hydrophilic or amphipathic soft segments that provide permeability to films and membranes prepared therefrom due to their lyophilicity, hydrophilicity and molecular weight, and hard segments that provide high cohesive energy reinforcement. The polymers of the invention may be cast into flexible sheets and/or hollow membrane shapes. The copolymers of this invention form strong, optically-clear, dense membranes which are selectively permeable to gases, ions, proteins and other macromolecules. The molecular weight cut-off of the membrane is controlled by varying the soft segment content, soft segment polarity/hydrophilicity and soft segment molecular weight.
2. Description of the Background
In general, polyetherurethane block or segmented copolymers exhibit good biocompatibility along with high strength and elastomeric properties. This unique combination of properties is due in part to the two-phase morphology of the polyurethane molecule. In a typical polyurethane, aggregated aromatic or aliphatic urethane or urea segments constitute a hard glassy or semicrystalline phase, while low glass transition temperature (Tg) oligomeric segments comprise the liquid-like, rubbery soft phase or segment. The morphology of a polyurethane depends on many factors, including hard and soft segment chemistry, segment polarity differences, hard segment content, and hard and soft segment molecular weights.
In both polyurethaneureas and polyurethanes, the chemistry of the soft segment affects the degree of phase separation in the polymer, which in turn affects its bulk and surface properties and subsequent biocompatibility. Polyurethaneureas, similar to the ones disclosed in this patent only as to their hard segment compositions, have been shown to be resistant to degradation in several applications (Paynter, et al., "The Hydrolytic Stability of Mitrathane, a Polyurethaneurea--An X-ray Photoelectron Spectroscopy Study", J. Biomed. Mater. Res. 22:687-698 (1988); Szycher, et al. "Blood Compatible Polyurethane Elastomers", J. Biomater. Appl. 2:290-313 (1987)).
The application of natural and synthetic polymer membranes to the separation of gaseous and liquid mixtures of low molecular weight has been reported in a number of reviews. Many studies of membrane permeability to simple low molecular weight (MW) permeants have been reported in which the composition of glassy-rubbery or crystalline-rubbery copolymers are varied. A polyurethane multipolymer membrane different from the one disclosed herewith has been shown to be water and salt permeable. In thermoplastic segmented block copolymers where one block or segment is glassy or crystalline (hard segment) and another is rubbery or liquid-like (soft segment), the permeation of molecules occurs primarily through the soft segment. The relatively impermeable hard segment, provides physical integrity to the polymer by virtue of its strong intermolecular interactions with like segments on adjacent molecules, even under conditions which may cause swelling of the soft segment.
Okkema, et al. discloses a series of polyether polyurethanes based on polyethylene oxide (PEO), polytetramethylene oxide (PTMO) and mixed PEO/PTMO soft segments suitable as blood contacting surfaces, but with a hard segment content of 55 wt %, too high to be useful in the present invention. (Okkema et al., "Bulk Surface and Blood-Contacting Properties of Polyurethanes Modified with Polyethylene Oxide", J. Biomater. Sci. Polymer. Edn.1(1):43-62 (1989)).
Takahara, et al. discloses the preparation of Segmented Poly (etherurethaneureas) (SPUU) with hydrophilic and hydrophobic polyether components. (Takahara et al., "Surface Molecular Mobility and Platelet Reactivity of (SPUUS) with Hydrophilic and Hydrophobic Soft Segment Components", J. Biomater. Sci. Polymer. Edn. 1(1):17-29 (1989)). Platelet adhesion and dynamic contact angle measured after adsorption of bovine serum albumin revealed that the SPUUs with hydrophilic soft segments had a non-adhesive surface.
Chen, et al. examines the relationship between structure and properties of polyether based polyurethanes. (Chen et al., "Synthesis, Characterization and Permeation Properties of Polyether Based Polyurethanes", J. Appl. Polym. Sci. 16: 2105-2114 (1972)). Of particular interest is the testing of the transport of water and low molecular weight salt through polymeric membranes made of elastomers that are block copolymers consisting of hard and soft segments, with the former acting as physical crosslinks.
U.S. Pat. No. 3,804,786 to Sekmakas discloses water-dispersible cationic resins, particularly polyurethane resins prepared by reaction of a resinous polyepoxide with a polyisocyanate to provide an hydroxy-functional polyurethane with tertiary amine functionality. These resins are useful for electrode position at the cathode.
U.S. Pat. No. 3,826,768 to Suzuki and Osonol discloses a process for preparing polyurethane compositions by dispersion of polyurethane-containing isocyanates made from polyols and organic isocyanates in water under specified conditions.
U.S. Pat. No. 3,852,090 to Leonard et al. discloses the utilization of a urethane film for waterproofing a breathable textile substrate.
U.S. Pat. No. 4,124,572 to Mao relates to thermoplastic polyurethanes prepared by a specified method. The thus produced elastomers are useful for automotive products, applications such as cattle ear tags, coatings and coated fabrics.
U.S. Pat. No. 4,183,836 to Wolfe, Jr. discloses a water-based polyurethane dispersion and its preparation by reacting an aliphatic diisocyanate with three critical active hydrogen compounds to form a pre-polymer containing carboxyl and free isocyanate groups, and then dispersing the pre-polymer in an aqueous medium with a tertiary amine and a diamine. These dispersions are useful in coating applications such as textile materials.
U.S. Pat. No. 4,190,566 to Noll et al. relates to non-ionic, water dispersible polyurethanes with substantially linear molecular structure and lateral polyalkylene oxide polyether chains containing ethylene oxide units of specified content.
U.S. Pat. No. 4,202,880 to Fildes et al., discloses sustained release delivery means comprising a biologically active agent, i.e., a drug, a linear hydrophilic block polyoxyalkylene-polyurethane copolymer, and optionally a buffer. A single hydrophilic soft segment is used. Only the hard segment is hydrophobic.
U.S. Pat. No. 4,202,957 to Bunk, et al. discloses polyurethane polyether-based elastomers which are thermoplastic and recyclable, and have increased high temperature resistance that makes them suitable for injection molding.
U.S. Pat. No. 4,224,432 to Pechhold et al. discloses a polyurethane comprising a reaction product of a polymerizate of tetrahydrofuran and an alkylene oxide, an organic polyisocyanate and a chain extender which is an aliphatic polyol or a polyamine. 2001.
U.S. Pat. No. 4,367,327 to Holker et al. relates to a breathable polyurethane film for coating fabrics to make them waterproof. The polyurethane film comprises in stoichiometric amounts a hard segment made of a low molecular weight diisocyanate with a difunctional compound, and a soft segment comprising polyethylene glycol. The mechanical properties of the film are improved by crosslinking with a triisocyanate.
U.S. Pat. No. 4,849,458 to Reed et al. discloses a hydrophilic, segmented polyether polyurethane-urea exhibiting increased tensile strength and elongation when wet with water. The polymers form clear films that are permeable to water vapor.
Many of these materials are segmented polyurethane elastomers. Some of them, moreover, have found biomedical applications virtually without being modified. However, despite their widespread use, many biomaterials were originally developed for nonmedical uses. In fact, most polyurethane materials were developed to satisfy high volume, industrial needs. A most notable example is DuPont's LYCRA.RTM. Spandex, a polyurethane utilized in the fabrication of circulatory support device components. This material was later sold under the trade name BIOMER.RTM. Segmented Polyurethane.
AVCOTHANE-51.RTM. resulted from the combination of two commercially available polymers, a silicone and a polyurethane, both of which are widely used as fabric coatings. AVCOTHANE-51.RTM. is utilized in biomedical devices such as an intra-aortic balloon. The sole improvements introduced for its biomedical applications were the use of highly purified starting materials, the filtration of the product solution and clean conditions for the fabrication of blood-contacting surfaces. Another biomedical polyurethane, AVCOTHANE-610.RTM., also called CARDIOMAT-610.RTM., and ANGIOFLEX.RTM. are presently being used in blood pumps and trileaflet heart valves.
The thermoplastic material PELLETHANE.RTM. was first applied to the manufacture of cannulae for blood vessels, and later of catheters. This material had originally been developed as an extrusion molding resin exhibiting superior hydrolytic stability than their polyester-based counterparts. Table 1 below lists some of the biomedical polyurethanes available in the U.S. market.
The known materials listed in Table 1 below may be essentially divided into two groups, where for each group one material is derived from the previous one, and so on.
TABLE 1 ______________________________________ Biomedical Polyurethanes ______________________________________ AVCOTHANE-51/CARDIOTHANE-51 (10% silicone) AVCOTHANE-610/CARDIOTHANE-610/ANGIOFLEX Biothane BIOMER/LYCRA Spandex/Mitrathane BPS-215 Estane 5714 Extrudable BIOMER PELLETHANE 2363/Renathane Superthane Tecoflex Texin Tygothane Vialon ______________________________________
If the polyesterurethanes, which exhibit low hydrolytic stability, are eliminated from the list, two classes of polyetherurethanes remain. These are the polyurethanes containing solely urethane groups, and polyurethaneureas, which also contain urea groups. Table 2 below lists some of the common reactants used in polyurethane synthesis.
TABLE 2 ______________________________________ Reactants of Biomedical Polyurethanes ______________________________________ POLYETHER H(O--CH.sub.2 --CH.sub.2 --CH.sub.2 --CH.sub.2 --).sub.n OH polytetramethylene oxide (PTMO) polytetramethylenetherglycol (PTMEG) polytetrahydrofuran (poly(THF)) DIISOCYANATE OCN--Ph--CH.sub.2 --Ph--NCO 4,4-diphenylmethane diisocyanate (MDI) CHAIN EXTENDERS HO--CH.sub.2 --CH.sub.2 --CH.sub.2 --CH.sub.2 --OH Polyurethanes: Butane Diol (BD) H.sub.2 N--CH.sub.2 --CH.sub.2 --NH.sub.2 Polyurethaneureas: Ethylene Diamine (ED) ______________________________________
The majority of useful biomedical elastomers are those prepared from polyether glycols. A most commonly-used polyether glycol is a product of the ring-opening polymerization of tetrahydrofuran (THF). This polyether is known mostly as polytetramethylenetherglycol (PTMEG), polytetramethyleneoxide (PTMO) and polytetrahydrofuran (poly(THF)). The present inventors have found that polyurethanes containing only soft segments of PTMO are impermeable to permeants as low as 180 daltons MW (glucose) and are, therefore, unsuitable for use in the present invention.
The most commonly used diisocyanate is 4,4-diphenylmethanediisocyanate (MDI). MDI-based polyurethane elastomers generally have physical and mechanical properties that are superior to polymers prepared from tolylene diisocyanate (TDI), or the aliphatic diisocyanates such as hexamethylene diisocyanate (HDI) and dicyclohexanediisocyanate (HMDI), a hydrogenated MDI analogue. Aliphatic diisocyanates produce non-yellowing polymers upon exposure to ultraviolet radiation and are thus extremely desirable for industrial and apparel coating applications. HMDI hard segments are often too miscible with the polyether segments to provide the degree of phase separation required to achieve optimal mechanical properties. This is particularly true at elevated temperatures, such as 37.degree. C., which significantly decrease the physical strength of a polymer. Phase separation is, therefore, important for attaining good physical properties in polyurethane elastomers. This relationship is discussed further below.
The reaction of isocyanate groups with low molecular weight difunctional reagents leads to chain extension, and to the formation of hard segments connecting the polyether soft segments through urethane groups. If the chain extender is a diol, the hard segment has repeat units connected by urethane groups, whereas if it is a diamine, the hard segment comprises urea groups. In the later case, the resulting polymer is referred to as a polyurethaneurea, although in common useage, both groups are often referred to as polyurethanes. Some of the properties of these elastomers are shown in Table 3 below.
TABLE 3 ______________________________________ Biomedical Polyurethane Properties POLYURETHANES POLYURETHANEUREAS e.g, PELLETHANE 2363.sup.1 e.g., BIOMER.sup.2 ______________________________________ moderate phase separation good phase separation thermoplastic solvent cast (unless H.sub.2 O extended) &gt;70A shore hardness low hardness/modulus possible moderate toughness extreme toughness moderate hysteresis/creep low hysteresis/creep good flex fife excellent flex life severe distortion in autoclavable autoclave ______________________________________ .sup.1 MDI/PTMO/BD .sup.2 MDI/PTMO/ED
The chemical composition of the permeable, rubbery phase of a block copolymer may be varied in this invention without resulting in a significant variation in its total volume fraction or glass transition temperature. Polyurethanes like the PELLETHANE 2363.RTM. series are moderately phase-separated thermoplastics generally having a shore hardness of 70A or higher. These polymers are reasonably tough and resistant to fatigue, but exhibit a high level of hysteresis or creep under load. These polyurethanes are usually unable to withstand autoclaving without distortion and molecular weight reduction. Polyurethaneureas like BIOMER.RTM. are more highly phase-separated elastomers which are generally manufactured in solution unless the diamine chain extender is completely replaced by water, as it is in the extrudable BIOMER.RTM. polymer. When the total content of hard segment is lowered, useful urea-containing urethanes are obtained. These are elastomers approaching natural rubber characteristics. Both BIOMER.RTM. and the polyether PELLETHANES.RTM. have pure PTMO soft segments and are unsuitable for use in the present invention.
A combination of high elongation at break and high ultimate tensile strength make the polyurethaneureas tougher than the corresponding polyurethanes. Their low hysteresis or creep properties, however, are probably their most outstanding feature. Polyurethaneureas exhibit excellent flex life when subjected to biaxial strain, such as in a blood pump. Finally, polyurethaneureas can withstand one or two autoclave cycles without evidencing a significant decrease in molecular weight or physical properties. This is indicative of a superior ability to retain their properties at elevated temperatures relative to their polyurethane analogues.
Although many polyurethanes and polyurethaneureas are available commercially, some of which were discussed above, none forms membranes of permeability, strength, flexibility and biocompatiblity required for growing cells by permitting the passage of nutrients, cell products and cell waste materials while preventing the passage of immunological or microbiological substances that might be detrimental to cell growth and the manufacture of cell products.